Supply-chain factors and antimicrobial stewardship

Abstract Efficient and secure supply chains are vital for effective health services worldwide. In low- and middle-income countries, the accessibility, affordability and availability of essential medicines, including antimicrobials, remain challenging. Ineffective supply chains often cause antimicrobial shortages, leading to inappropriate use of alternative agents and increasing the risk of antimicrobial resistance. Shortages, coupled with insecure supply chains, also encourage the infiltration of substandard and falsified medicines, leading to suboptimal treatment and further promoting antimicrobial resistance. Addressing antimicrobial supply-chain issues should be considered a key component of antimicrobial stewardship programmes. We have explored the link between medicine supply chains and antimicrobial use in seven focus countries: Kenya, Malawi, Nigeria, Sierra Leone, Uganda, United Republic of Tanzania and Zambia. We explored country medicine supply-system structures, national medicine supply-chain policy documents and global study reports. Our aim was to develop evidence-based strategies to enhance the effectiveness and efficiency of the medicine supply chains in supporting antimicrobial stewardship efforts. Better management of medical supply chains involves rational selection, quantification, forecasting, procurement, storage, distribution, use and stock management of antimicrobials. Important supply-chain considerations include pooled procurement networks to ensure consistent pricing of quality-assured antimicrobials, and improved resource utilization and information exchange among relevant stakeholders. We propose adaptable recommendations for integrating medicine supply chains as an essential part of antimicrobial stewardship programmes, with a call for action at the local, regional and national levels in low- and middle-income countries.


Introduction
Antimicrobial resistance disproportionately affects low-and middle-income countries. 1 An often-missing component of governance surrounding antimicrobial resistance in many countries is medicine procurement and inventory control. Antimicrobial stewardship programmes, which aim to optimize the use of antimicrobials, may not succeed unless medicine procurement is effective, efficient and secure, ensuring the timely availability of appropriate antimicrobial products. 2 Health supply chains are the processes and operations required to get products and medicines from manufacturers to health-care staff and patients at the right place, price, time, cost, quality, efficacy and quantity. Strong and secure supply chains save lives. They are the fundamental building blocks of national welfare systems and are necessary for the achievement of the sustainable development goals. The coronavirus disease 2019  pandemic drew attention to the importance of resilient supply chains in national emergency response efforts. 3 A continuing challenge in low-and middle-income countries is inadequate access to essential medicines and medical supplies, including antimicrobial medicines. 4 Highincome countries also report challenges with medicine supplies, but these countries frequently have advanced reporting systems and, in many cases, easier access to substitute medicines. 5 Despite this access, a survey conducted by the European Association of Hospital Pharmacists revealed that 86% of hospital pharmacists across 30 countries (463 out of 537 respondents), reported that medicine shortages were a current problem in their hospitals, with the majority reporting that this problem occurred on a daily or weekly basis. 6 Antimicrobial shortages hinder timely access to effective therapies and can be drivers for the emergence of antimicrobial resistance and excess mortality, particularly in low-and middle-income countries. 7 Infiltration of substandard and falsified medicines into the medicine supply system can occur via unauthorized suppliers or due to inadequate enforcement of regulations. Commodity insecurity in lower-resource settings therefore also has an impact on the quality and effectiveness of antimicrobials.
There is limited published information specifically on the supply chains for antimicrobials and access to these medicines in low-and middle-income countries. In this article we explore the impact of medicine supply chains on antimicrobial use, focusing on seven countries of the Commonwealth Partnerships for Antimicrobial Stewardship programme. We issue a call to action on incorporating supply-chain considerations into Policy & practice Supply chains and antimicrobial stewardship Nduta Kamere et al.
antimicrobial stewardship policies and processes. Table 1 provides an overview of the medicine supply chains of the seven focus countries: Kenya, Malawi, Nigeria, Sierra Leone, Uganda, United Republic of Tanzania and Zambia. We highlight the similarities and differences among them in the type of procurement agency; the public service agency responsible for the procurement, warehousing and distribution of drugs and medical supplies; and the availability of a national essential medicine list for public institutions. We based our overview on a purposeful search of each country's medicine supply-system structures, national medicine supply-chain policy documents, global study reports and a rapid literature search of PubMed ® articles published between 2015 and 2021.

Countries overview
All seven countries obtain, fund and distribute essential medicines through a combination of health ministries, nongovernment organizations and the private sector. The existing systems are classified as tier systems, single agencies or devolved. Except for Nigeria, every country has a centralized supply chain. All seven countries have existing national essential medicine lists. Kenya, United Republic of Tanzania and Zambia have WHO AWaRe (Access, Watch, Reserve) categories of antimicrobials recommended in their national essential medicine lists. All seven countries face challenges in the management of health products and technologies that are familiar to many highincome countries. Challenges reported in medicine supply chains include: inadequate quality assurance; weak regulation; poor enforcement of laws; unavailable and unaffordable medicines; transport and storage infrastructure; poor information and logistics management; inadequate human resources; and inadequate financing. [9][10][11][12][13][14][15] Kenya Local supply chains for medicines and medical supplies in Kenya are dependent on three supply chains within the health sector: the health ministry; non-profit procurement agencies; and private distributors and wholesalers. 16 The health ministry provides stewardship over the supply chain for health products and technologies as guided by the Health Policy 2014-2030. 17 The health ministry, with support from implementation partners, has rolled out several capacity-building initiatives. The initiatives focus on improving the accuracy of medication quantification and forecasting; optimizing commodity procurement and storage practices; and enhancing the effectiveness of the logistics management information system to better track and manage the flow of medicines and supplies. 9 Shortages of essential medicines in Kenya 10 have resulted in substitution of publicly funded first-line treatments with second-line drugs, leading to increased out-of-pocket expenditure on medicines by patients using the private health sector. Higher drug costs can lead to patients purchasing substandard and falsified medicines through unlicensed and illegal pharmacies or unregulated websites. To help address the situation, hospitals in Kenya conduct ABC (always, better, and control) and VEN (vital, essential, and non-essential) analysis of their medicine use. Research into current patient and epidemiological patterns helps Kenya to understand the specific health needs of its population and inform its medication selection and prescribing practices. [18][19][20]

Malawi
The supply chain for essential medicines in Malawi follows a rigorous process that ensures compliance with the Public Procurement Act (2003) and the Public Procurement Guidelines (2004). The Central Medical Stores Trust sources medicines and other health commodities in accordance with the policies and guidelines of the Director of Public Procurement. Essential medicines are distributed from a central warehouse to three regional medical stores which supply public health facilities. 11 Malawi has other parallel supplychain systems for essential medicines, especially relating to disease programmes such as tuberculosis, malaria and reproductive health. Chronic stockouts of medicines at the central medical stores and in health facilities remain a challenge. 11

Nigeria
There are two key agencies in Nigeria involved in medicine supplies: the National Agency for Food and Drug Administration and Control; and the Pharmacists Council of Nigeria. The pharmaceutical services division within the Nigerian food and drug authority is part of the health ministry and regulates and monitors the pharmaceutical supply chain, supporting access to quality medicines in Nigeria. 21 Nigeria supplies agencies have faced difficulties with selection of medicines and vaccines, procurement and distribution of medicines, inventory management and storage infrastructure. 12 These challenges have led to stock-outs of essential medicines.

Sierra Leone
The National Medical Supplies Agency of Sierra Leone, formerly the Directorate of Dr ugs and Medical Supplies, undertakes the transparent and costeffective procurement, warehousing and distribution of drugs and medical supplies on behalf of all public institutions throughout the country. 7,22 Several additional parallel supply chains exist, including those for specific programmatic areas such as human immunodeficiency virus infection, tuberculosis, malaria, nutrition and neglected tropical diseases. This fragmentation dilutes resources and capacity, duplicates activities and creates administrative inefficiencies. 23 The impact of the COVID-19 pandemic on the local pharmaceutical industr y resulted in severe drug shortages and medicine insecurity in the country due to the restrictions imposed on cross-border imports. 24 Sierra Leone depends solely on the import of pharmaceutical commodities, which creates an opportunity for substandard and falsified medicines to enter the legitimate medicine supply chain. 24 Sierra Leone's National Medical Supplies Agency also partners with external agencies to develop efficient procurement, distribution and inventory systems. 13

Uganda
The management of essential medicines and health supplies in Uganda is guided by the Essential Medicines and Health Supplies Management Manual of 2018. The National Medical Stores provide the public health-care facilities with the core antibiotics. 25 As in many other low-and middleincome countries, Uganda faces challenges with enforcement of regulations, creating multiple nodes of entry for medicines into the market that may accelerate the proliferation of substandard and Supply chains and antimicrobial stewardship Nduta Kamere et al.
falsified products. 26 Challenges to achieving sustainable medicine use in Uganda include poor forecasting and planning of medical supplies, overly bureaucratic procurement guidelines, delays in shipping of medicines and poor supply-chain infrastructure. 27 As a result, patients, health-care providers and regulatory agencies have reported fragmented access to essential medicines, inappropriate use of medicines, poor quality and inappropriate disposal of medicines and inadequate information.

United Republic of Tanzania
The United Republic of Tanzania has a centralized procurement system for medicines. The Medical Stores D e p a r t m e nt , u n d e r t h e P u b l i c Procurement Act 2004 and Regulations 2005, is empowered to advertise, receive, evaluate and award successful bidders for government contracts. The price and quality of the product are given equal consideration when awarding the tender. 28 The country has a higher use of antimicrobials compared with many other countries worldwide. Contributing factors include a relatively higher burden of infectious diseases; limited diagnostic services in health facilities; widespread availability of antibiotics without prescription; and the unexplained use of certain antibiotics in the animal health sector. 14

Zambia
Zambia has a three-tier public sector distribution system for essential drugs. The primary distribution of drugs and other health commodities is managed by the Zambia Medicines and Medical Supplies Agency, formerly Medical Stores Limited. The secondary distribution of commodities falls under the responsibility of district health management teams reporting to the health ministry. The national pharmacovigilance unit under Zambia's Medicines Regulatory Authority leads and coordinates the pharmacovigilance or drug safety monitoring programme in the country. 29 According to Zambia's national h e a l t h s t r a t e g i c p l a n , t h e k e y planning issues for the medicines, vaccines and medical supplies sector are weak coordination mechanisms and accountability in supply-chain management, and an inadequate quality

Missing links
Challenges within antimicrobial supply chains worldwide, including in lowand middle-income countries, make forecasting and mitigating antimicrobial shortages difficult. 7 Research findings suggest that a combination of factors create barriers to access that prevent millions of people from receiving the antibiotics they need. These factors include weak, underfunded health systems, failure to reimburse suppliers, unreliable supply chains and high out-of-pocket costs. 30,31 Affordability of medicines has also affected decisions on antimicrobial use in Kenya and northern United Republic of Tanzania. 32 Shortages and stock-outs can be prevented by strengthening the supply chain for medicines across all stages, from active pharmaceutical ingredients to finished products, including ensuring robust quality of pharmaceutical ingredients and all raw materials. 33 The fragility of supply chains for medicines was highlighted during the COVID-19 pandemic. Closures of country borders, spikes in demand for medicines and supply interruptions overwhelmed governments, pharmaceutical companies and health systems. 34 Such conditions not only affect access to essential medicines, but also present opportunities for substandard and falsified medicinal products to infiltrate the supply chain. These medicines enter through various channels, such as counterfeiters, unauthorized distributors or other groups who may take advantage of weaknesses in the supply chain. 35 For example, the availability of cardiovascular disease medicines is reported to be low in rural western Kenya, fuelling the rise of substandard and falsified medicines in this category. 36 A n t i m i c r o b i a l s , e s p e c i a l l y antimalarials and antiretrovirals, are the most commonly falsified medicinal products worldwide. 37 Suboptimal antimicrobial doses caused by the use of poor quality or counterfeit products accelerate the development of antimicrobial resistance. In many low-and middleincome countries, patients can purchase antibiotics without prescription. Studies show that over-the-counter antibiotics may be used as incomplete regimens or to treat non-bacterial illnesses. 32 The problem is exacerbated by shortages and frequent stock-outs of essential medicines, including antimicrobials.
Supply-chain security is therefore an important factor in antimicrobial resistance. 37 Poor inventory management, limited logistics management information systems, inadequate storage systems and weak quality control can increase the risk of substandard and falsified antimicrobials entering supply chains. In many low-and middle-income settings, ineffective drug distribution systems increase the chances of expired drugs entering the pharmaceutical supply chain, creating waste, and compromising quality and health outcomes relating to the safe and effective use of medicines. 12,38 Furthermore, inadequate access to basic health services may lead patients to obtain supplies from less-regulated sources, such as informal markets, increasing their risk of acquiring substandard and falsified medicines. 35 The main functions of countries' national medicines regulatory authorities include: (i) control of pharmaceutical products through registration and postmarketing surveillance; (ii) control of activities by licensing and inspection of manufacturers, importers, exporters, wholesalers, distributors, pharmacies and retail outlets; (iii) control of clinical trials; and (iv) control of promotion of pharmaceuticals. However, in 2010 the World Health Organization (WHO) estimated that 34 out of 38 national medicines regulatory authorities in sub-Saharan Africa were not enforcing basic regulatory functions. 39 The task of the regulatory authorities is complicated by the complexity of the international supply chains, whereby intermediate traders and brokers operate along transnational routes outside stringent regulatory supervision. Furthermore, the major donors to medical programmes do not always apply consistent quality criteria for the selection of the medicines that they fund. International and national procurement agencies play an important role in defining the quality of medicines available at country level. 39 Drug shortages, combined with inappropriate prescribing and use of antimicrobials, accelerate the development of antimicrobial resistance and hence reductions in antimicrobial effectiveness. 31 Ac c e ss to me d i c i ne s , i nclu d i ng antimicrobials, is hampered by supplychain bottlenecks such as inadequate medicine selection, use, procurement and inventor y management. 40 In Malawi, supply-chain bottlenecks have been reported to prevent community health workers from accessing essential medicines for vulnerable children in poor and rural areas. 40 Health-care workers can improve supply chains by implementing better supply-chain management. 41 Pharmacists have an important role to play. 41 Storage and distribution are essential components of medicine supply chains. Pharmacists can help to design and implement processes to strengthen supplychain security by regulating appropriate medicine distribution and reporting of substandard and falsified medicinal products. Various assessments conducted in Zambian health facilities identified secondary distribution, from district stores to health facilities as the main bottleneck in the distribution system. 29 Inappropriate storage conditions during transport, such as exposure to high temperatures or moisture, may affect the stability of antimicrobials and lead to suboptimal doses of the drugs, further fuelling antimicrobial resistance. 42 These processes are often managed by pharmacists, who can advise on and monitor storage conditions and hence play a role in antimicrobial stewardship. Countries can also reduce overuse of antimicrobials by ensuring adequate vaccination coverage for relevant diseases. 43,44 A secure and effective vaccine supply chain (including adequate coldchain maintenance where appropriate) is fundamental to achieving vaccination goals.

Looking ahead
Addressing supply-chain challenges requires consistent efforts at the global, national and regional levels, building on existing partnerships and legislation. We need to address ways to pool the procurement of medicines, improve the forecasting of supply needs and increase the commitment to improving processes and resources. Measures could include appropriate storage conditions, implementing efficient transportation and distribution systems, and maintaining reliable quality control measures throughout the supply chain. Sustainability of medicine supply chains remains an elusive goal that is yet to be integrated into discussions. 45 There is evidence that a multi-pronged approach is effective to improve the supply chain of medicines in hospitals. Such an approach includes proactive management of the supply chain, accurate forecasting of supply needs and the implementation of therapeutic interchange policies to Supply chains and antimicrobial stewardship Nduta Kamere et al.
ensure the availability of substitute medications when needed. 30,46 Ensuring access to medicines of a suitable quality is an important aspect of effective health systems. Proper inventory management regulated by pharmacists can result in a consistent supply of the medicines and vaccines necessary for the successful implementation of antimicrobial stewardship programmes. Building inventory management principles into antimicrobial stewardship will support countries to acquire medications that meet good manufacturing practices and are free from adulteration and tampering.
We can improve antimicrobial ste wardship and st rengt hen t he knowledge and evidence base of factors contributing to antimicrobial resistance through ongoing surveillance and research. 2 Evidence-based research can inform effective policy guidance to improve many aspects of the supply and use of antimicrobials, including supply-chain management. Furthermore, implementation of WHO essential medicine policies is important for reducing antimicrobial misuse in lowand middle-income countries. 47 Such efforts could improve access to medicines by increasing stock availability and decreasing the prevalence of substandard and falsified antimicrobials. 48 It is important to ensure that, as far as possible, appropriate Access and Watch antibiotics are available for the most common infections within hospitals across Africa. The WHO AWaRe (Access, Watch, Reserve) antibiotic book offers clear and evidence-based recommendations on the appropriate antibiotic choice, dosage, administration route and treatment duration for over 30 prevalent clinical infections in both primary health care and hospital settings. The book's

Local organizations
• Optimize appropriate antimicrobial use through pre-service and in-service training for health-care workers on effective medicine procurement, inventory control and distribution management. • Designate local resource mobilization as a priority area in health ministries to build and sustain the medicine supply-chain systems.
• Engage the right human workforce into the local supply chains to ensure reliability of the systems (supply planning experts, procurement professionals, commodity specialists, pharmacists, pharmaceutical technologists, quality assurance staff, security personnel, storage professionals and logistics experts). • Establish or empower medicine and drug and therapeutics committees to act as an oversight mechanism in health-care facilities.
• Establish antimicrobial stewardship programmes that include supply-chain management as an essential component, to ensure rational antimicrobial selection, quantification and forecasting, procurement, storage, distribution, use and stock management of antimicrobials.

Regional organizations
• Streamline and strengthen national medicine supply-chain systems.
• Use pooled procurement networks, to ensure consistent pricing of quality-assured antimicrobials and to improve resource utilization and information exchange between organizations. • Harmonize drug master files and specifications required for antimicrobial resistance surveillance. • Standardize pre-qualified supply mechanisms, including those from manufacturers, to ensure constant availability of antimicrobials.
• Increase the number of well-designed studies into medicine supply-chain management to identify gaps and challenges in low-and middleincome countries. • Increase quality assurance programmes that conduct routine inspections of manufacturers, suppliers and warehouses to ensure medicines meet international quality standards.

National organizations
• Consider approaches such as the Lomé Initiative to criminalize the trafficking of falsified medical products.
• Increase regulatory capacity and reporting mechanisms to detect and tackle substandard and falsified medical products.
• Strengthen national medicines regulatory agencies and harmonize legislation, taking a collaborative approach through the African Medicines Agency. • Increase local production of antimicrobials to strengthen supply-chain resilience and reduce the risk of infiltration of substandard and falsified antimicrobials. • Encourage more national policies and government regulatory frameworks for the essential infrastructure, such as national warehousing, distribution and transport of quality-assured health products. • Incorporate analysis of bottlenecks into national supply chains to identify underlying causes and human behaviours that influence procurement agencies and practices. • Integrate digital health systems interventions, with the implementation and scale-up of logistics management information system software, to improve the forecasting, monitoring, evaluation, tracking and planning of medicine supply chains. • Ensure that appropriate Access and Watch antibiotics are available for key diseases relevant to the national context and the World Health Organization Model list of essential medicines. • Set up consumption surveillance systems for antimicrobials to ensure rational antimicrobial selection and use, particularly lower down the supply chain. • Develop and implement antimicrobial national action plans to include supply-chain management. • Ensure antimicrobial stewardship initiatives address over-prescribing and inappropriate prescribing; improve patient adherence to treatment regimens; and address potential environmental contamination, for example through inappropriate disposal of antimicrobials. • Update mechanisms for the review and reporting of substandard and falsified medicines, providing a user-friendly and safe environment to encourage reporting and facilitate feedback.

Policy & practice
Supply chains and antimicrobial stewardship Nduta Kamere et al.
information aligns with the antibiotic recommendations outlined in the WHO Model list of essential medicines and WHO Model list of essential medicines for children, as well as the WHO AWaRe antibiotic classification. 8 The African antibiotic treatment guidelines for common bacterial infections and syndromes also provide care workers with expert recommendations for antimicrobial selection, dosage and duration of treatment for common bacterial infections and syndromes among paediatric and adult patient populations in Africa. 49 To ensure the continuity of medication supply, there is an increasing demand for and evidence to support the use of digital technology as a tool to monitor stock levels, which provides accurate and real-time feedback. 42 Post-marketing surveillance and pharmacovigilance is needed to detect substandard and falsified medicinal products. Efforts are also required to improve medicine quality by strengthening the medicine distribution chain; ensuring the use of quality-assured drugs through improved pharmaceutical governance; and strengthening the technical capacity of regulatory laboratories, particularly in poor and rural communities. 48 Approaches such as the Lomé Initiative -a binding agreement to criminalize the trafficking of substandard and falsified medical products in some African countries -may also increase access to quality medicines. 50 We propose that the basic principles of medicine supply-chain systems should be included in capacity-building for antimicrobial stewardship teams and health-care personnel at local, national and global levels. The managers of procurement systems within a country are responsible for ensuring the continuous availability of essential quality-assured medicines at an affordable price. Implementing monitoring and evaluation systems for antimicrobial resistance and antimicrobial use as part of national action plans could contribute to the use of quality-assured medicines, and reduce the distribution of substandard and falsified medical products. 51

Proposed recommendations
In the absence of stringent national and international regulatory oversight, ensuring the quality of medicines becomes a choice rather than a duty. As a result, there is a risk that poor-quality medicines will enter the supply chain, causing harm to individuals and public health. 46 We propose that medicine supply chains be considered an integral part of antimicrobial stewardship, and we issue a call to action to address the issue at the local, regional and national levels in low-and middle-income countries (Box 1). We present adaptable recommendations for establishing antimicrobial stewardship programmes that include management of medical supply chains at local levels; streamlining and strengthening national supply-chain systems; and improved resource utilization and information exchange among relevant stakeholders. These actions will ensure that adequate supplies of quality antimicrobials are available, allowing health professionals to select appropriate treatments and contributing to safe and effective use of antimicrobials.  Une meilleure logistique requiert une certaine rationalité dans la sélection, la quantification, la planification, l'approvisionnement, le stockage, la distribution, l'utilisation et la gestion des stocks d'antimicrobiens. Dans ce contexte, plusieurs éléments sont importants tels que les réseaux d'achats groupés, qui assurent la stabilité des prix pour des antimicrobiens de qualité garantie, ou encore l'optimisation des ressources et l'échange d'informations entre les acteurs concernés. Nous formulons des recommandations ajustables en vue de rendre les chaînes d'approvisionnement en médicaments incontournables dans les programmes de gestion des antimicrobiens, avec un appel à agir à l'échelle locale, régionale et nationale dans les pays à revenu faible et intermédiaire.